PROJECT SUMMARY/ABSTRACT Eosinophilic esophagitis (EoE) is an atypical form of food allergy, in that the patients do not experience immediate symptoms in the mouth, in the skin or in the esophagus following exposure to relevant foods. Nonetheless many or most of the children with EoE get better, both symptomatically and histologically, over 2- 3 months on a diet excluding specific foods including cows' milk (CM) and/or wheat. It is known that many children with EoE have detectable, but low-titer IgE antibodies (Ab) to CM, wheat or egg proteins. It has also been reported that adults with EoE have IgG4 Ab specific for relevant foods. Recently we have demonstrated that children with EoE have high or very high titers of IgG4 Ab to proteins from CM or wheat. These responses can be as high as 100 g/ml of IgG4 Ab, which is as high as any specific IgG4 responses previously reported. In comparison with an age-matched unselected cohort there was a very strong association (odds ratios as high as 15) between sIgG4 to CM proteins ? 10 g/ml and a diagnosis of EoE. This association was particularly strong among boys aged 10-18, although there were too few girls and young children in the cohort to draw firm conclusions about the effects of age or sex on the IgG4 response to CM proteins. Thus, the main objective here is to expand the size of the cohort to be able to gain more evidence about the effects of age, sex and/or CM consumption on specific IgG4 levels. This will include a larger number of young children with EoE, but also males and females extending into early adulthood. As part of the case-control design the study will involve recruitment of age-similar young children and young adults that are unselected for allergic disease. The results from these studies will form a foundation for future prospective investigations into whether measurement of serum IgG4 and/or IgE to specific foods could have utility as a non-invasive tool for diagnosis and/or management of EoE. An additional objective will be to investigate the significance of our recent finding that over 10% of adolescent children from an unselected birth cohort had high-titer IgG4 Ab to CM proteins. Despite being less prevalent than in EoE children, this finding suggests that the immune response that contributes to EoE is relatively common in the general population and raises the possibility that esophageal eosinophilia (or latent EoE) may be more prevalent in the community than currently appreciated. To address this, control adults who are identified as having high-titer sIgG4 Ab specific for CM and/or wheat proteins will be invited for esophagoscopy and biopsy.